Summary of Research Project:

"Functions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular Endothelium"

Our research focuses on the molecular mechanisms by which the pulmonary artery (and the pulmonary arterial endothelial cell or PAEC in particular) responds to injury, such as inadequate oxygen availability (“hypoxia”). It is widely appreciated that, in response to hypoxia, the PAEC undergoes metabolic adaptations important in the development of pulmonary hypertension (PH), a complex disease state characterized by increasing pulmonary arterial pressures. If untreated, PH can lead to heart failure, volume overload, and death. However, further details of the molecular processes by which hypoxia causes PH remain enigmatic.

We have hypothesized that non-canonical, non-protein coding genes may control these key events in disease progression. Endogenous microRNA molecules (miRNA) are such recently described non-canonical regulatory factors. They are small, non-protein coding RNA molecules that are largely conserved through evolution. It is estimated that greater than thirty percent of all human genes are regulated by miRNA in some context, but the functions of only a few specific miRNA molecules have been characterized to date.

In the nineteenth century, Louis Pasteur first described a fundamental cellular response to hypoxia, resulting from a metabolic shift from mitochondrial respiration to glycolysis. Over the past two years, we have identified microRNA-210 (miR-210) as an essential regulator of the metabolic processes that govern this “Pasteur effect,” via repression of the iron-sulfur cluster assembly proteins ISCU1/2 and consequent perturbation of cellular respiration during hypoxia. These results have established an entirely novel mechanism that clarifies our fundamental understanding of the cellular adaptation to hypoxia.

In our proposed studies, we plan to determine whether such control of cellular metabolism by miR-210 promotes the development of PH via disrupting mitochondrial function and altering levels of toxic reactive oxygen species and nitric oxide. Using a combination of bioinformatics, cell-culture based assays, and unique mouse and rat models of PH, this proposal will provide a comprehensive description of the miR-210/ISCU1/2 regulatory axis in the pulmonary arteries of living mammals. In doing so, this work is expected to improve our fundamental understanding of pulmonary vascular injury and may offer novel possibilities for diagnosis and treatment of PH to benefit this growing and historically long-suffering population of patients.

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